The transcription factor cAMP response element binding protein (CREB) has been implicated in the long-term neuronal plasticity associated with addiction. While CREB is expressed in many cells throughout the brain, very little is known about the relative concentrations of CREB protein in various brain regions. Studies in which CREB levels have been altered, either constitutively throughout the brain via gene targeting or transiently in specific brain regions, demonstrate variable roles for this protein in mediating reinforcing properties of drugs of abuse. To investigate the complex nature of CREB function in addiction, we examined the distribution of CREB protein in the nucleus accumbens (NAc) and ventral tegmental area (VTA), two brain regions that are part of the well-defined mesolimbic dopamine pathway involved in reward processing. Our data demonstrate significantly more CRE binding activity and CREB protein in the NAc compared to levels present in the VTA of wild-type mice. Phospho-CREB levels are increased in the NAc of both wild-type and CREB aD mutant animals after cocaine. However, morphine-induced increases of phospho-CREB levels are seen in the VTA of wild-type mice but not CREB aD mutant mice. Consequently, the 90% reduction of CREB in CREB aD mutant mice differentially affects CREB phosphorylation and induction of downstream targets of CREB in the NAc and VTA.
The cAMP-response element binding protein (CREB) is involved in antidepressant action, but the role of related CRE-binding transcription factors in the behavioral and endocrine responses to antidepressants is unclear. Alternative transcription of the cAMP response element-modulator (CREM) gene yields activator and repressor isoforms, including the strong repressor inducible cAMP early repressor (ICER). ICER is highly expressed in hypothalamic tissues and upregulated after electroconvulsive seizure. Thus, ICER may be a novel mediator of antidepressant action at endocrine and/or behavioral levels. Here we establish that both subchronic and chronic desipramine (DMI) treatments upregulate hypothalamic ICER expression in wild-type mice. Behavioral responses to DMI in the forced swim and tail suspension tests are unchanged in mice lacking ICER. However, the ability of DMI to suppress an acute corticosterone response after swim stress is compromised in ICER-deficient mice, suggesting that increased hypothalamic ICER mRNA after DMI treatment may be required for suppression of corticosterone release. To investigate the mechanism underlying this response, we measured corticotropin releasing factor (CRF), an upstream modulator of corticosterone release. Using real-time quantitative PCR, we establish that hypothalamic CRF expression is significantly reduced after swim exposure in DMI-treated wild-type mice, however DMI is unable to blunt hypothalamic CRF expression in ICER-deficient mice. Furthermore, we demonstrate that ICER is enriched in CRF-expressing neurons in the paraventricular nucleus of the hypothalamus. These data indicate that ICER is required for DMI to reduce stress-induced corticosterone release through regulation of hypothalamic CRF expression, revealing a novel role for ICER in antidepressant regulation of the hypothalamic-pituitary adrenal axis.
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